Somatostatin (SS), a tetradecapeptide characterized in 1972 from hypothalamic extracts, inhibits the secretion of growth hormone (GH), insulin, glucagon, and several gastrointestinal hormones and possesses a variety of neurotropic actions as well. SS-like biological and immunological activity is found in a variety of organs (pancreas, brain, gastrointestinal tract) in all vertebrate classes. We intend to isolate and chemically and/or immunologically characterize SS from several sources including the normal and diabetic pancreas and will investigate the possibility that the reported big form of SS might represent a pro-SS. We will determine the nature of the substances responsible for SS-like immunoreactivity in serum and, if feasible, will develop methods for the routine assay of serum SS. We propose to investigate the physiologic regulation and the mechanisms of SS biosynthesis and secretion. The possibility that these processes are altered in pathologic states such as diabetes will be investigated. Clinical findings indicate that somatostatin administered intravenously or subcutaneously lowers plasma glucagon and thus improves glucose homeostasis in patients with diabetes mellitus. The chronic use of somatostatin itself to treat diabetes presents practical problems due to its multiple actions and short duration of biological activity. We have recently synthesized and biologically tested analogs of somatostatin which are more potent than somatostatin, exhibit extended duration of biological activity, and possess selected actions--e.g., analogs more potent to inhibit the secretion of glucagon than insulin. We will continue to develop analogs with improved potency, duration of action and selectivity and, furthermore, will continue our search for antagonists of SS. We will investigate the biological and toxicological properties of such analogs and intend to make these analogs available for clinical studies in various disease states, particularly in diabetes mellitus.